2015-P: 14-3-3zeta Is Required for PKA-Dependent Lipolysis
Bibliographic record
Abstract
The molecular scaffold, 14-3-3?, was previously found to be essential for visceral adipogenesis, but its contributions to the function of mature adipocytes is not known. As it can regulate the activities of metabolic effectors, we hypothesized that 14-3-3? also has essential roles in adipocyte function. 3T3-L1 adipocytes and mouse models were used to study if 14-3-3? regulates lipolysis. Depletion of 14-3-3? by siRNA abrogated glycerol and free fatty acid (FFA) release from 3T3-L1 cells treated with Isoproterenol (ISO, 1 μM), Forskolin (FSK, 10 μM), and dibutyryl cAMP (1 mM). In contrast, over-expression of 14-3-3? potentiated ISO-mediated FFA release. Knockdown of 14-3-3? did not affect cAMP generation in ISO- and FSK-treated 3T3-L1 cells, but mRNA levels of lipases (Atgl, Hsl, and Magl) and Pparg were reduced, suggesting a loss of adipocyte identity. Decreased activation and total expression of PKA substrates, including Hsl and CREB, were detected in 14-3-3?-depleted 3T3-L1 cells. Taken together, these data suggest that 14-3-3? is necessary for lipolysis from 3T3-L1 adipocytes. To understand adipocyte-specific roles of 14-3-3?, tamoxifen (TMX)-inducible, adipocyte-specific 14-3-3? knockout (adi14-3-3?KO) mice were used. Four weeks after TMX exposure (5 days, 50 mg/kg), no effects on body weight were found. After an overnight fast, adi14-3-3?KO mice displayed impaired lipolysis following i.p CL-316,243 (1 mg/kg) injections. In contrast, transgenic over-expression of 14-3-3? did not affect lipolysis. Adi14-3-3?KO mice also displayed glucose intolerance following i.p. glucose (2 g/kg). Real-time PCR confirmed significant reductions in Atgl, Hsl, and Pparg mRNA levels in adi14-3-3?KO mice, suggesting impaired adipocyte function. Collectively, these results demonstrate essential functions of 14-3-3? in facilitating lipolysis and, potentially, adipocyte maturity. Future studies are aimed at understanding how 14-3-3? regulates other aspects of adipocyte function, including diet-induced expansion of fat mass. Disclosure A. Oppong: None. Y. Mugabo: None. G.E. Lim: None. Funding Canadian Institutes of Health Research
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".